Process for the preparation of 2-aminomethylpyridine derivative

ABSTRACT

Process for the preparation of 2-aminomethylpyridine derivative of general formula (I), in which: n represents 0, 1, 2 or 3; X is halogen atom; Y may be the same or different and may be a halogen atom, a halogenoalkyl, a alkoxycarbonyl or a alkylsulphonyl

CROSS REFERENCE TO RELATED APPLICATIONS

The present applicationis a 35 U.S.C. §371 national phase conversion ofInternational Application No. PCT/EP2003/014862 filed Nov. 18, 2003,which claims priority of European Patent Application No. 02356235.8filed Nov. 20, 2002.

The present invention relates to a novel process for the preparation of2-aminomethylpyridine derivative which is useful as intermediatecompound for the preparation of pesticides, starting with benzophenoneand glycine alkyl ester hydrochloride.

Patent application WO 99/42447 discloses the preparation of2-aminomethylpyridines starting from benzophenone glycine imine alkylester. This document does not disclose a method for the preparation ofbenzophenone glycine imine alkyl ester.

Certain methods for the preparation of benzophenone glycine imine alkylester have been reported in Journal of Peptide Research (2000), 55(4),page 300–307. This article discloses the reaction of benzophenone iminewith alkyl glycinate hydrochloride to prepare benzophenone glycine iminealkyl ester. The use of benzophenone is not disclosed in that document.The use of benzophenone imine presents the drawback in that it isexpensive. Furthermore, this compound converts into the benzophenonecompound during the preparation of 2-aminomethylpyridine compounds thusresulting in an additional step in the process to convert benzophenoneinto benzophenone imine before recycle, which is undesirable on acommercial plant.

We have now found an alternative method to prepare 2-aminomethylpyridinederivatives which overcomes these problems and which is applicable toindustrial scale operation.

Accordingly, the present invention relates to a process for thepreparation of a 2-aminomethylpyridine derivative of general formula (I)or a salt thereof:

in which:

-   -   n represents 0, 1, 2 or 3,    -   X is halogen atom,    -   Y may be the same or different and may a halogen atom, a        halogenoalkyl, a alkoxycarbonyl or a alkylsulphonyl;        said process comprising:

-   (A)—a first step according to reaction scheme 1:

in which benzophenone (BP) is reacted with glycine alkyl esterhydrochloride (GAE.HCl) at reflux in a non polar solvent, said solventbeing capable of forming an azeotrope with water, in the presence of anacid catalyst and a trialkylamine base, in a BP/GAE.HCl molar ratio offrom 1 to 4, to provide a benzophenone glycine imine derivative (BPGI);

-   (B)—a second step according to reaction scheme 2:

in which:

-   -   X, Y and n are as defined above,    -   z is a leaving group,        comprising the reaction of the benzophenone glycine imine        derivative (BPGI) solution obtained in step one with a pyridine        derivative (Py-z) in the presence of a dry inorganic base, in        the presence of a catalyst and an aprotic polar solvent, the        mixture being heated at reflux, to provide a pyridine glycine        imine derivative (PyGI);

-   (C)—a third step according to reaction scheme 3:

in which X, Y and n are as defined above comprising the addition to theprevious pyridine glycine imine derivative (PyGI) solution of an aqueoushydrochloric acid at a temperature up to 25° C., in a HCl/PyGI molarratio of at least 1, to provide a pyridine glycine ester hydrochloridederivative (PyGE.HCl);

-   (D)—a fourth step comprising the conversion of the pyridine glycine    ester hydrochloride derivative (PyGE.HCl) into a compound of general    formula (I) by heating under reflux of water.

For the purposes of the present invention:

-   Alk represents a C₁–C₅ alkyl moiety, preferably ethyl;-   haloalkyl means C₁–C₆ alkyl moiety substituted by one or more    halogen atoms;-   alkoxycarbonyl means C₁–C₆ alkoxycarbonyl. Suitable examples of such    a moiety may be methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl    and i-propoxycarbonyl;-   alkylsulphonyl means C₁–C₆ alkysulphonyl;-   “Catalyst” means a compound which is used in an amount of 0.01 to    0.2 molar equivalent, preferably from 0.01 to 0.1 molar equivalent    of the respective reagent or intermediate compound;-   a halogen atom may be a bromine atom, a chlorine atom, a iodine atom    or a fluorine atom.

During the preparation of PyGE.HCl from PyGI according to the presentinvention, benzophenone can be recovered and ready to be directlyrecycled for benzophenone glycine imine alkyl ester preparation.According to the present invention, benzophenone does not need to berecycled into benzophenone imine, avoiding an expensive additional step.Furthermore, the yield of product obtained by the process according tothe present invention is greater than the yield achievable with theprocesses known from the prior art.

The present invention relates to a process for the preparation ofcompound of general formula (I). Preferably, the differentcharacteristics of compound of formula (I) may be chosen independentlyfrom each other as being:

-   as regards X, X is chlorine;-   as regards n, n is 1;-   as regards Y, Y is haloalkyl; more preferably, Y is trifluoromethyl.

More preferably, the present invention relates to a process for thepreparation of compound of general formula (I) in which:

-   X is chlorine;-   n is 1;-   Y is trifluoromethyl.

The process of the present invention is particularly suitable for thepreparation of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine.

The first step (step A) of the process according to the presentinvention requires the use of a solvent which is capable of forming anazeotrope with water. Suitable solvent includes toluene or ethylbenzene.Step A of the process according to the present invention requires theuse of an acid catlayst, preferably paratoluenesulfonic acid catalyst.Step A of the process according to the present invention requires alsothe use of a trialkylamine base. The preferred trialkylamine base isN,N-diisopropyl N-ethylamine.

The second step (step B) of the process according to the presentinvention comprises the reaction of the benzophenone glycine iminederivative (BPGI) obtained in step one with a pyridine derivative(Py-z), wherein z is a leaving group, preferably a halogen atom and morepreferably a chlorine atom. Step B of the process according to thepresent invention requires the use of a dry inorganic base. Suitable dryinorganic base includes dry K₂CO₃ or NaH. Step B of the processaccording to the present invention requires the use of a catalyst,preferably a phase transfer catalyst. Suitable phase transfer catalystmay be NEt₄Br. Step B of the process according to the present inventionalso requires the use of an aprotic polar solvent. Suitable solvent maybe propionitrile.

The third step (step C) of the process according to the presentinvention is carried out at a temperature up to 25° C., preferably at atemperature of from 20 to 25° C. Step C is carried out in a HCl/PyGImolar ratio of at least 1, preferably in a HCl/PyGI molar ratio of from1 to 5.

The product stream obtained in the different steps of the processaccording to the present invention may be treated to separate and torecycle useful compounds. Such post treatment steps may be carried outaccording to methods well known by the man ordinary skilled in the art.Particularly, the mixture obtained following to step A may be cooleddown and washed with water to dissolve trialkylamine base hydrochloridesalt. The two liquid phases may then be separated. The bottom aqueouslayer containing the trialkylamine base hydrochloride salt may beseparated and treated with aqueous sodium hydroxide to recovertrialkylamine base for recycle. The solvent layer which contains theBPGI and the excess of benzophenone may be dried by azeotropicdistillation of the solvent and water. The dry solution of BPGI insolvent may then be ready for the coupling reaction with Py-z.

On completion of step B, the aprotic polar solvent is distilled undervacuum for possible recycle. The mixture of PyGI, non polar solvent andexcess dry inorganic base may be cooled down at about 20° C. and thenwashed with water to separate the two phases. A bottom aqueous layercontaining excess dry inorganic base may be discarded. The solution ofPyGI in non polar solvent and the excess of benzophenone from theprevious step may then be ready for the acidification reaction of thestep C.

On completion of the step C, two phases may be separated. The bottomaqueous phase containing PyGE.HCl which is ready for the decarboxylationstep (step D), and a top non polar solvent phase containingbenzophenone. The non polar solvent and benzophenone may be recoveredfor recycle to the BPGI preparation.

The conversion of PyGE.HCl into compound of general formula (I)according to part D of this process may be performed by known methodssuch the one described in WO 99/42447 herein incorporated by reference.

During the preparation of PyGE.HCl from PyGI according to the presentinvention, benzophenone can be recovered for direct recycle intobenzophenone glycine imine alkyl ester preparation. According to thepresent invention, benzophenone does not need to be recycled intobenzophenone imine, avoiding an expensive additional step.

Thus, according to another aspect of the present invention there isprovided a process for the preparation of pyridine glycine esterhydochloride derivative (PyGE.HCl) according to reaction schemes 1 to 3as above described.

The present invention will now be illustrated with reference to thefollowing examples.

EXAMPLE 1 Preparation of benzophenone glycine imine ethyl ester

In a 1 litre glass reactor equipped with a distillation section and aDean and Stark separator, 182 g (1 mole) of benzophenone, 70.1 g (0.5mole) of glycine ethyl ester hydrochloride, 4.75 g (0.05 mole) ofparatoluenesulfonic acid and 249 g of toluene were loaded.

The mixture was heated at 110–115° C. at atmospheric pressure to give agood reflux in toluene. 97 g (1.05 mole) of N,N-diisopropyl N-ethylamine was added by pump over 4 hours. During the reaction, water wasformed and was distilled off as water-toluene azeotrop. Water wasdecanted in the Dean and Stark separator and toluene was returned to thereactor. Reaction was pursued for 1 hour after the end of the amineaddition and completion of the reaction was monitored by liquidchromatography.

When reaction was complete, the reaction mixture was cooled down to 20°C. The mixture was then washed with 335 g of water and the 2 liquidphases were separated by decantation. The bottom aqueous phasecontaining all N,N-diisopropyl N-ethyl amine hydrochloride was kept fortreatment by aqueous sodium hydroxide to recover N,N-diisopropyl N-ethylamine for recycle.

The upper toluene phase containing benzophenone glycine imine ethylester and the excess benzophenone was concentrated during whichoperation water was removed as an azeotrope with toluene. The drysolution, of benzophenone glycine imine ethyl ester in toluene wasassayed by liquid chromatography: a 91% yield of benzophenone glycineimine ethyl ester was obtained with respect to glycine ethyl esterhydrochloride.

EXAMPLE 2 Preparation of ethylN-(diphenylmethylene)2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate

In a glass reactor equipped with a distillation section and a Dean andStark separator, 185 g (3 molar equivalent) of potassium carbonate and300 g of toluene were loaded. Potassium carbonate was dried of water byrefluxing in toluene and distilling off water-toluene azeotrop at a pottemperature of 110° C. 150 g of toluene were removed.

To the dry suspension of potassium carbonate, 4.75 g (0.05 molarequivalent) of tetraethylammonium bromide, 310 g of propionitrile and380 g (1 molar equivalent of BPGI intermediate) of the previous solutionof dry benzophenone glycine imine ethyl ester in toluene were added. Themixture was heated at reflux (105° C.), and 99 g (1 molar equivalent ofbenzophenone glycine imine ethyl ester intermediate) of2,3-dichloro-5-trifluoromethyl-pyridine was added by pump over 3 hours,maintaining reflux and separating the condensate in the Dean and Starkcondensator, returning solvent to the reaction vessael and discardingwater. The reaction completion was monitored by liquid chromatography.Reflux with water removal was continued for a further 3 hours after theend of the pyridine addition. Propionitrile was then distilled off undera reduced pressure of 300 mbar. The reaction mixture was cooled down to20° C. 315 g of water was added and the 2 liquid phases were separated.The bottom aqueous phase contains all the unreacted potassium carbonateand was discarded. The upper toluene phase of ethylN-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinatewas assayed by liquid chromatography. A yield of 85% in ethylN-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinatewith respect to 2,3-dichloro-5-trifluoromethyl-pyridine was obtained.

EXAMPLE 3 Preparation of ethyl2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate

To the ethylN-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinatesolution in toluene obtained in the previous example, 290 g of aqueous10% hydrochloric acid were added at 20° C. The reaction was stirred for1 hour. Conversion of ethylN-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinateto ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate hydrochloridesalt was monitored by liquid chromatography for completion.

Two liquid phases were separated. The bottom aqueous phase containingethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate hydrochloridesalt was separated and was ready for the following decarboxylationreaction (preparation of2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride). The toporganic phase contains all the benzophenone from ethylN-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinateand the excess from the BPGI preparation, and was recovered for recycleat step 1. A 93% recovery yield of benzophenone with respect to the 182g (1 mole) introduced in beinzophenone glycine imine ethyl esterpreparation was obtained.

EXAMPLE 4 Preparation of2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride

The previous aqueous solution of ethyl2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate was heated underreflux for 7 hours. CO₂ formed during the reaction was vented off. Afterreaction completion, the recovery yield of 2-aminomethylpyridinehydrochloride with respect to PyGI was 86%.

1. Process for the preparation of a 2-aminomethylpyridine derivative ofgeneral formula (I) or a salt thereof:

in which: n represents 0, 1, 2 or 3, X is halogen atom, Y may be thesame or different and may be a halogen atom, a halogenoalkyl, aalkoxycarbonyl or a alkylsulphonyl; said process comprising: (A)—a firststep according to reaction scheme 1:

in which benzophenone (BP) is reacted with glycine alkyl esterhydrochloride (GAE.HCl) at reflux in a non polar solvent, said solventbeing capable of forming an azeotrope with water, in the presence of anacid catalyst and a trialkylamine base, in a BP/GAE.HCl molar ratio offrom 1 to 4, to provide a benzophenone glycine imine derivative (BPGI);(B)—a second step according to reaction scheme 2;

in which: X, Y and n are as defined above, z is a leaving group,comprising the reaction of the benzophenone glycine imine derivative(BPGI) solution obtained in step one with a pyridine derivative (Py-z)in the presence of a dry inorganic base, in the presence of a catalystand an aprotic polar solvent, the mixture being heated at reflux, toprovide a pyridine glycine imine derivative (PyGI); (C)—a third stepaccording to reaction scheme 3;

in which X, Y and n are as defined above comprising the addition to theprevious pyridine glycine imine derivative (PyGI) solution of an aqueoushydrochloric acid at up to 25° C., in a HCl/PyGI molar ratio of at least1, to provide a pyridine glycine ester hydrochloride derivative(PyGE.HCl); (D)—a fourth step comprising the conversion of the pyridineglycine ester hydrochloride derivative (PyGE.HCl) into a compound ofgeneral formula (I) by heating under reflux of water.
 2. Processaccording to claim 1, characterised in that X is chlorine.
 3. Processaccording to claim 1, characterised in that n is
 1. 4. Process accordingto claim 1, characterised in that Y is haloalkyl.
 5. Process accordingto claim 4, characterised in that Y is trifluoromethyl.
 6. Processaccording to claim 1, characterised in that X is chlorine, n is 1 and Yis trifluoromethyl.
 7. Process according to claim 6, characterised inthat compound of general formula (I) is2-aminomethyl-3-chloro-5-trifluoromethylpyridine.
 8. Process accordingto claim 1, characterised in that, in the first step, the acid catalystis paratoluenesulfonic acid catalyst.
 9. Process according to claim 1,characterised in that, in the first step, the solvent capable of formingan azeotrope with water is toluene or ethylbenzene.
 10. Processaccording to claim 1, characterised in that the trialkylamine base isN,N-diisopropyl N-ethylamine.
 11. Process according to claim 1,characterised in that, in the second step, z is a halogen atom. 12.Process according to claim 11, characterised in that z is a chlorineatom.
 13. Process according to claim 1, characterised in that, in thesecond step, the dry inorganic base is K₂CO₃ or NaH.
 14. Processaccording to claim 1, characterised in that, in the second step, thecatalyst is a phase transfer catalyst.
 15. Process according to claim14, characterised in that the phase transfer catalyst is Net₄Br. 16.Process according to claim 1, characterised in that, in the second step,the polar solvent is propionitrile.
 17. Process according to claim 1,characterised in that, in the third step, the temperature is of from 20to 25° C.
 18. Process according to claim 1, characterised in that, inthe third step the HCl/PyGI molar ratio is of from 1 to
 5. 19. Processfor the preparation of

in which: n represents 0, 1, 2 or 3, X is halogen atom, Y may be thesame or different and may a halogen atom, a halogenoalkyl, aalkoxycarbonyl or a alkylsulphonyl; said process comprising: (A)—a firststep according to reaction scheme 1;

in which benzophenone (BP) is reacted with glycine alkyl esterhydrochloride (GAE.HCl) at reflux in the presence of an acid catalystand a trialkylamine base, in a non polar solvent, said solvent beingcapable of forming an azeotrope with water, in a BP/GAE.HCl molar ratioof 1 to 4, to provide a benzophenone glycine imine derivative (BPGI);(B)—a second step according to reaction scheme 2;

in which: X, Y and n are as defined above, z is a leaving group,comprising the reaction of the benzophenone glycine imine derivative(BPGI) solution obtained in step one with a pyridine derivative (Py-z)in the presence of a dry inorganic base, in which is added a catalystand an aprotic polar solvent, the mixture being heated at reflux, toprovide a pyridine glycine imine derivative (PyGI); (C)—a third stepaccording to reaction scheme 3;

comprising the addition to the previous pyridine glycine iminederivative (PyGI) solution of an aqueous hydrochloric acid at up to 25°C., in a HCl/PyGI molar ratio of at least 1, to provide a pyridineglycine ester hydrochloride derivative (PyGE.HCl).